Method and apparatus for the time sharing of multiple channel analysis means

ABSTRACT

New and improved method and apparatus for the time sharing of multiple channel fluid sample analysis means are provided and comprise operatively associated light source, light sensitive detector means, digital logic means, detector and logic means timing and control means, detector circuit means, multiple channel fluid sample analysis result read-out means and read-out means timing and control means, respectively, said detector means is constituted by a single light-sensitive detector means in the nature of a photo-multiplier tube, and said detector circuit means comprises a single, temperature stabilized log diode and amplifier. An embodiment is disclosed wherein said light source is automatically and precisely tunable light source. In operation, the apparatus is effective to repeatedly scan said multiple channel analysis means and provide simultaneous recordings of the analysis results which are linear with regard to the respective fluid sample optical densities on said analysis result read-out means. The apparatus is applicable for use with multiple channel analysis means which include only colorimeters, and for use with multiple channel analysis means which include colorimeters and fluorimeters. The advantageous disposition of the analysis means on the manifold of operatively associated fluid sample supply and treatment means is also made possible by the apparatus of the invention.

United States Patent Kassel et al.

[s41 METHOD AND APPARATUS FOR THE TIME SHARING oF MULTIPLE CHANNELANALYSIS MEANS [72] Inventors: Aaron Knssel, Tarrytown; Donald F.Kopelman, New York, both of N.Y.

[73] Assignee: Technicon Instruments Corporation,

' Tarrytown, N.Y.

[22] Filed: Aug. 6, 1970 [21] Appl. No.: 61,582

[52] US. Cl. ..356/18l, 356/l88, 356/195, 356/205 [51] Int. Cl..G01j3/46, Gln 21/22 [58] Field of Search ..356/180, 181, 184, 186,188, 356/195, 205, 208

[56] References Cited UNITED STATES PATENTS 3,504,981 4/1970 Malvin..356/195 X 2,594,514 4/ 1952 Sweet ..356/205 3,241,432 3/1966 Skeggs etal. ..356/181 X 3,503,683 3/1970 lsreeli et al. ..356/181 X 3,379,0944/1968 Bertram ..356/226 3,480,786 11/1969 Kottman ..250/227 X 2,990,3396/1961 Frank et al ..356/208 X 3,447,876 6/1969 Barringer ..356/1883,487,225 12/1969 Button ..356/205 3,520,624 7/ 1970 Johnson et a1...356/205 X 2,773,414 12/1956 Green ..356/205 X 3,486,821 12/ 1969Westhaver ..356/226 X 3,455,637 7/1969 Howard ..356/205 X [151 3,697,185[4.51 Oct. 10,1972

,551,058 '12/1970 Doddsetal ..356/188X Primary Examiner-Ronald L. WibertAssistant Examiner--V. P. McGraw Attorney-S. P. Tedesco 7] ABSTRACT Newand improved method and apparatus for the time sharing of multiplechannel fluid sample analysis means are provided and compriseoperatively associated light source, light sensitive detector means,digital logic means, detector and logic means timing and control means,detector circuit means, multiple channel fluid sample analysis resultread-out means and read-out means timing and control means,respectively, said detector means is constituted by a singlelight-sensitive detector means in the nature of a photomultiplier tube,and said detector circuit means comprises a single, temperaturestabilized log diode and amplifier. An embodiment is disclosed whereinsaid light source is automatically and precisely tunable light source.In operation, the apparatus is effective to repeatedly scan saidmultiple channel analysis means and provide simultaneous recordings ofthe analysis results which are linear with regard to the respectivefluid sample optical densities on said analysis result read-out means.The apparatus is applicable for use withmultiple channel analysis meanswhich include only colorimeters, and for use with multiple channelanalysis means which include colorimeters and fluorimeters. Theadvantageous disposition of the analysis means on the manifold ofoperatively associated fluid sample supply and treatment means is alsomade possible by the apparatus of the invention.

13 Claims, 16 Drawing Figures CHANNELS 3 THROUGH 2 50 2B CHANNEL 2SAMPLE 2e CHANNEL l TO GATE SAMPLE/HOLD v m MODULES FOR CHANNELS 76 2osmnoucu I2 I05 Q 14 I6 2m SAMPL s :34 I '94 mm 232 250 4 2 MODULE 2 t['88 i 4 HAMELI F I84 190 smiPLE/ 255 I96 0 a2 234 I 254 21s MODULE aIs2 205 as was L f elf; AMFLE P39 200 as 236 l 258 MODULE NNEL FF AMESAMPLE/ 254 i 4 0 MwuLE 2 o RECORDERS FOR CHANNELS 3 THROUGH I2 CHANNELS2l2 3 THROUGH l2 PATENTEDUBT 10 I972 CHANNELS 3 THROUGH l2 SHEET 1 UF 9JREFERENCEE SAMPLE E 8 CHANNEL 2 v REFERENCE E SAMPLE I--.b

CHANNEL I MOTOR I I72 I70 T O CHANNELS SAMPLE/ HOLD MODULE SAMPL HOLDMODULE SAMPLE/ HOLD MODULE SAMPLE/ HOLD MODULE 3 THROUGHIZ AARON TO GATESAMPLE/HOLD MODULES FOR CHANNELS 3 THROUGH I2 RECORDERS FOR CHANNELS 3THROUGH 12 INVENTORS KASSEL DONAL KOPE'LMAN v BY ATTORNEY PKTENTEDMI 10I972 SHEET 2 0F 9 INVENTORS ATTORNEY R A, &4 W. m. Q)

P'A'IENTEnw 10 I912 3,697,185

SHEET 3 [IF 9 FROM FLUID SAMPLE SUPPLY AND TREATMENT SAMPLE SUPPLY ANDTREATMENT l FROM FLUID W MEANS CHANNEL 7J SU I 38 TO WA$TE INVENTORSAARON KASSEL D ALD KOPELMAN ATTORNEY PATENTED II 10 I 2 13.697, 1 85 sum5 OF 9 cHA NELs 3 THROUGH L2 50 3 24 48 48 44 REFERENCEE CHANNEL 2 2 :1SAMPLE v F IIREFERENOE CHANNEL l 3 SAMPLE 38 280 no 0 DIGITAL LOGIC v f224 TO GATE SAMPLE/HOLD MODULEs FOR CHANNELS 3 THROUGH I2 20s SAMPLE/232 HOLD 25o MODULE 230 CHANNEL l sAMPLE/ HOLD 7 258 MODULE SAMPLE/ 238258 HOLD 236 F MODULE CHANNEL 2 220 SAMPLE/ I HOLD MODULE 240 TOREOORDER FOR cHANNELs EOTEEQSSEL'SZ 3THROUGH l2 Fl G 6 lNvENToRs I AARONKAS ONALD KOPELMAN BY 4 J ATTORNEY PATENTEDnm 10,1912

SHEET 7 OF 9 CHANNELS 3 THROUGH 12 4s :5 5e 3 REFERENCE E-A 42 (T SAMPLE[A 42 28 REFERENCEE-n 4O 40 22 3 SAMPLE P 38 O 25 38 330 40 40 HO vi) 1-v 306 TUNABLE LIGHT 322 I J I MOTOR I SOURCE 312 DIGITAL II E: T0 /33e 1ANALOG I CONVERTER I B6 338 I l 64 SHAFT I663 DGITAL 323- POSITION ,lesLIOGIC I6 I INDICATOR I 1 I72 I -222 I 224 1' 22s I K READ-OUT READ-OUTL'GHT DETECTOR TIMING FOR 1 Cmcun AND CHANNELS E R X I CONTROL ITHROUGHl2 f I88 I 202 t \IQ INVENTORS AARON KASSEL 8 DONA D KOPELMA R l d,

ATTORNEY PATENTEDBB w 1972 3 e97. 185

SHEET 8 BF 9 Q TO SAMPLE FLUID i FLOW CELLS FOR CHANNELS 3 THROUGH I2SAMPLE E SAMPLE c 40 26 3s 38 n2 L y 366 LIGHT 71 Y SENSITIVE MOTORDETECTOR I62 FA INVENTORS 72 AARON KASSEL w I08 I60 70 BY DONA DKOPELMAN l4 v I A 4 364 4, ATTORNEY PATENTED EH IH 3.691185 SHEET 8 F 9.

TO SAMPLE FLUID F FLOW CELLSFOR CHANNELS 3 5 THROUGH I2 44 44 \HSAMFPLEk2 40 w SAMPLEE 40 I 22 IIzb H \JI I 322, I 72 70 304 4 TUNABLE LIGHTSENSITIVE MOTOR SOURCE DErEcToR -TO SAMPLE FLUID 284 FLOW CELLS EoRCHANNES 3 5O THROUGH l2 4 44 28 J 2 4 L- 44 46v 42 42 g: J TIME 4:22:58r Q c- 288 40 2 6 I INVENTORS 38 AARoN KASSEL 4 BY DONALD KOPELMANATTORNEY l METHOD AND APPARATUS FOR THE TIME SHARING F MULTIPLE CHANNELANALYSIS MEANS BACKGROUND OF THE INVENTION conditions wherein theoperational environment thereof cannot be closely controlled.

More specifically, such unduly high apparatus costs are due in part tothe need for relatively expensive componentsin the nature ofhigh-quality D.C. amplifiers and precisely regulated power supplies, andthe requisite repetition thereof and of other components in the natureof log diodes, operating and detecting circuits, appropriate opticalelements, photo-detection elements, and manually. adjustable aperturesand the like to enable adjustment fordiffering light energy levels. v

Too,.in many instances, the relevant apparatus of the prior art requirea precisely temperature controlled environment for accurate and reliableoperation, and .it is believed clear that the provision of the same canprove very expensive and quite unwieldy. In addition, many oftherelevant apparatus of the prior art provide the "results of theanalyses performed thereby in the form of log functions to thus increasethe costof recording the same and render the interpretation thereofsomewhat more involved.

Also, the fact that many of the relevant methods and apparatus of theprior art are not adaptable for use with multiple channel analysis meanswhich comprise different forms of analysis means and are not, in anyevent, readily modifiable for use with multiple channel analysis meanshaving differing numbers of analysis channels.

Further, and in instances wherein said prior art multiple channelanalysis apparatus take the form of a multiple channel colorimeterhaving a plurality of flow cells for utilization in operativeconjunction with automatic fluid sample supply and treatment means inthe nature of those shown and described in U.S. Pat. No. 3,241,432issued Mar. 22, 1966 to Leonard T. Skeggs et al. and assigned to theassignee hereof, the disposition of said flow cells at locations remotefrom the manifold of said fluidsample supply and treatment means withattendant requirement for relatively long hydraulic and electricalconnections therebetween give rise to additional increases in apparatuscoststand difficulties in providing for accurate and reliable operationthereof.

OBJECTS OF THEINVENTION time sharing of multiple channel analysis meanswhich are of relatively low cost and which embody a high degree ofaccuracy and reliability of operation.

Another object of this invention is the provision of method andapparatus, as above, which are accurately and reliably operableindependent of ambient temperature changes within a reasonable range ofthe latter.

Another object of this invention is the provision of method andapparatus, as above, which provide for analysisresults in a more direct,less costly and more interpretable form.

Another object of this invention is the provision of method andapparatus, as above, which are adaptable for use with multiple channelanalysis means which include more than one form of analysis means.

Another object of. this invention is a provision of method andapparatus, as above, which are of significant versatility in that thesame may be readily modified for operation with a variety of multiplechannel analysis means having differing numbers of analysis channels.-

Another object of this invention is the provision of apparatus, asabove, which require the use of only readily available components ofproven dependability in the fabrication thereof to provide for longperiods of satisfactory,substantially maintenance-free apparatusoperation. l

A further object of this invention is the provision of method andapparatus, as above, which, when utilized with multiple channel, fluidsample colorimetric or similar analysis means having fluid sample flowcells, enable the disposition of said flow cells at optimum locationsrelative to the fluid sample supply and treatment means which supplysaid fluid samples thereto.

A farther object of this invention is the provision of method andapparatus, as above, which are particularly adaptable to the timesharing of multiple channel colorimetric analysis means for thecolorimetric analysis of a plurality of blood sample quotients as aresupplied thereto from blood sample supply and treatment means of thetype disclosed in said U.S. Pat. No. 3,241,432.

SUMMARYOF THE INVENTION As disclosed herein for use with multiplechannel, fluid sample analysis means, the apparatus of the inventiongenerally comprise operatively associated light sensitive detectormeans, digital logic means, detector and logic means timing and controlmeans, detector circuit means, multiple channel fluid sample analysisresult read-out means and read-out means timing and control means,respectively. In operation, as more specifically described, light from acommon source is routed by light pipes to and through the respectiveanalysis means channel flow cells, and therefrom to a stationary lighttransmission directing disc. A rotating light pipe scanner scans saiddisc and transmits the light therefrom insequence to a singlephotomultiplier tube. Concomitantly, a rotating timing disc providesanalysis channel 'indiciathrough fiber optic photo-cell reader means tothe digital logic means of the light being transmitted at any givenpoint in time to the photomultiplier tube. The resultant output currentsfrom the photomultiplier tube are applied in sequence across a singlelog diode, amplified by appropriate amplifier means, and

applied as voltage signals from the latter to the read-out means timingand control means. Temperature stabilization means are provided torender the operation of said log diode and said amplifier meanssubstantially independent of ambient temperature changes. Concomitantlywith the application of said voltage signals to said read-out meanstiming and control means, digital signals are applied thereto from saiddigital logic means and are effective to operate the former inaccordance with said analysis channel indicia to activate theappropriate channel of the read-out means and provide an accurate,readily reproducible recording of the analysis results which is linearwith fluid sample optical density. In one disclosed embodiment, all ofsaid analysis means channels are constituted by colorimetric analysismeans while, in other disclosed embodiments, said analysis meanschannels may comprise both colorimetric and fluorimetric analysis means.An embodiment is disclosed which requires the operative positioning ofsingle fiber optic or light pipe means, only. relative to said lightsource to provide for increased optical efficiency, and an embodiment isdisclosed which utilizes an automatically turnable light source toenable the elimination of optical filters, simplification of said lightsensitive detector means, and provide for even greater increase inoptical efficiency.

A specific application of the apparatus of the invention to fluid samplesupply and treatment apparatus of the type shown and described in U.S.Pat. No. 3,241,432 is disclosed which makes possible the advantageousdisposition of the analysis means flow cells directly on the supply andtreatment apparatus manifold to thus minimize the requisite hydraulicand electrical path lengths.

DESCRIPTION OF THE DRAWINGS The above and other objects and significantadvantages of this invention are believed made clear by the followingdetailed description thereof taken in conjunction with the accompanyingdrawings wherein:

FIG. 1 is a generally schematic diagram of a first embodiment ofapparatus constructed in accordance with the teachings of thisinvention;

FIG. 2 is a front plan view of the stationary light transmission disc ofFIG. 1;

FIG. 3 is a rear plan view of the rotating timing disc of FIG. 1;

FIGS. 4A and 4B are flow diagrams depicting the simultaneous flow ofsample fluid quotients through the sample fluid flow cells of FIG. 1;

FIGS. 5A through 5D are timing diagrams illustrating the operation ofthe apparatus of FIG. 1;

FIG. 6 is a generally schematic diagram of a second embodiment of theapparatus of the invention which is utilizable for simultaneouscolorimetric and fluorimetric analysis;

FIG. 7 is a generally schematic diagram of a third embodiment of theapparatus of the invention which enables the operative positioning ofsingle fiber optic or light means, only, relative to the apparatus lightsource;

FIG. 8 is a generally schematic diagram of a fourth embodiment of theinvention wherein the light source is constituted by a turnable lightsource;

FIG. 9 is a front plan view of a modified form of the stationary lighttransmission directing disc of the invention;

FIG. 10 is a generally schematic diagram of the apparatus of FIG. 1utilizing the modified form of stationary light transmission directingdisc of FIG. 9;

FIG. 11 is a generally schematic diagram of the apparatus of FIG. 8utilizing the modified form of the stationary light transmissiondirecting disc of FIG. 9; and

FIG. 12 is a generally schematic diagram of an advantageous applicationof the apparatus of FIG. 1 or FIG. 6 for use with automatically operablefluid sample treatment and supply means.

DETAILED DESCRlption of the invention New and improved apparatus for thetime sharing of fluid sample analysis means constructed and operative inaccordance with the teachings of our invention are indicated generallyat 10 in FIG. 1 and may be seen to comprise colorimetric fluid sampleanalysis means as indicated generally at 12, light sensitive detectormeans as indicated generally at 14, digital logic means as indicatedgenerally at 16, detector and logic means timing and control means asindicated generally at 17, detector circuit means as indicated generallyat 18, fluid sample analysis result read-out means as indicatedgenerally at 19, and read-out means timing and control means asindicated generally at 20, which are respectively operatively arrangedas shown.

The fluid sample analysis means 12 comprise reference fluid flow cells22 and 24, and sample fluid flow cells 26 and 28, and each of said flowcells may take the form, for example, of that shown and described inU.S. Pat. No. 3,345,910 issued Oct. 10, I967 to Seymour Rosin, et al.and assigned to the assignee hereof. As such, it may be understood thateach of said flow cells will have a fluid flow path which forms a lightpath of precisely predetermined length b form ed therein to extendtherethrough between opposed, transparent flow cell end walls asspecifically identified at 30 and 32 for sample fluid flow cell 26,only.

The respective reference and sample fluid flow cells are operativelyarranged in pairs to form colorimetric fluid sample analysis channels.More specifically, it may be understood that sample fluid flow cell 26and reference fluid flow cell 22 are operatively arranged to formcolorimetric analysis channel 1 as indicated, while sample fluid flowcell 28 and reference fluid flow cell 24 are likewise operativelyarranged to form colorimetric analysis channel 2 as indicated. For useas described in detail hereinbelow in the substantially simultaneously,automatic colorimetric analysis of a series of fluid samples with regardto 12 distinct constituents of each of said samples, it may beunderstood that 12 of such colorimetric fluid sample analysis channelswould be provided which would, of course, require the provision of anadditional 20, non-illustrated flow cells to provide the additionalchannels 3 through 12 as clearly indicated in FIG. l.v

Further included in the fluid sample colorimetric analysis means 12 is asuitable light source 34 which is, of course, arranged to be energizedfrom any suitable, nonillustrated source of appropriate electricalpower. Since, the apparatus 10 is operative at relatively highopticalefficiency, the light source 34 may take a simpler form than thatnormally required for colorimetric analysis, and may be operated at alower voltage, for longer lamp life, from relative simple power supplymeans to thus eliminate the need for a relatively expensive regulatedlamp power supply, all to significant ad vantage as should be obvious.

Suitable light transmission means are indicated generally at 36 and areprovided to transmit the light from the light source 34 for passagethrough the light paths of each of the provided flow cells and, uponexit therefrom, to transmit said light to the detector means timing andcontrol means 16 for transmission from the latter to the lightsensitivedetector means 14. More specifically, said light transmissionmeans 36 may be understood to take the form of suitable fiber opticmeans and, as depicted in FIG. 1 may readily be seen to comprise alightpipe 38 which extends as shown from the light source 34 to transmitthe light therefrom through sample fluid flow cell 26 of colorimetricanalysis channel I, a light pipe 40 which extends as shown from saidlight source to transmit the light therefrom through reference fluidflow cell 22 of colorimetric analysis channel 1, a light pipe 42 whichextends as shown from said light source to transmit the lighttherefromthrough sample. fluid flow cell 28. vof colorimetric analysischannel 2, and a light pipe 44 which extends as shown from said lightsource to transmit the light therefrom through reference fluid flow cell24 of colorimetric analysis channel 2. The light pipes which function totransmit the light from light source 34 to and through the respectivenon-illustrated reference-and sample fluid flow cells of the remainingcolorimetric analysis channels 3 through l2 are generally illustrated bylight pipes 48 and 50.

An optical filter 45, having a bandpass which is appropriate to thecolorimetric quantitative determination of the fluid sample constituentof interest with regard to colorimetric analysis channel 1, isinterposed as shown in the respective light pipes 38 and 40 of saidcolorimetric analysis channel; while an optical filter 46, having abandpass which isappropriate to the colorimetric quantitativedetermination of the fluid constituent sample of interest with regard tocolorimetric analysis channel 2 is disposed as shown in the light pipes42 and 44 of said colorimetric analysis channel. In like manner, it maybe understood that an optical filter having a bandpass which isappropriate, in each instance, to the fluid sample constituent ofinterest with regard to the remaining, nomillustrated colorimetricanalysis channels 3 through 12, is interposed as described in therespective light pipe paths thereof.

All of the provided light pipes are collected as shown at the respectivelight exit ends of the provided flow cells into a fiber-optic orlightpipe bundle 56 which in turn extends, as shown, into operativerelationship with the detector and logic means timing and control means17. Further included in light transmission means 36 is a light pipe orfiber-optic bundle 58 comprising light pipes 60, 62, 64, 66 and 68 whichrespectively extend as a bundle from the light source 34 to divergetherefrom as shown adjacent the respective light exit extremitiesthereof at the detector and logic means timing and control means 17.

Referring now to the detector and logic means timing and control means17, the same may be seen to comprise a constant speed, electric drivemotor 70 having a drive shaft 72 which may be arranged, for example, torotate at a constant 1,800 rpm. A rotating timing disc 74 is affixed asindicated to the motor drive shaft 72 adjacent the remote extremitythereof so as to be rotateable therewith. As best seen in FIG. 3, therear surface 76 of the timing. disc 74 is binary coded throughappropriate treatment of said disc surface to provide for portions orareas thereon which are substantially light reflective, and portions orareas thereon which are substantially light absorbtive ornon-reflective. More specifically, and for use as disclosed herein withautomatic fluid sample colorimetric analysis means including twelvecolorimetric analysis channels, the timing disc surface of interest maybe seen to be divided into five, generally circular concentric bands asindicated at 76, 78, 80, 82, and 84, respectively. The said bands are inturn respectively divided radially as shown into 12 band portions asindicated at 1 through 12 to provide one of said band portions for eachof said colorimetric analysis channels, and saidband portions are inturn each radially divided as shown into a reference fluid band portionand a sample fluid band portion as indicated in each instance at R and Srespectively.

- If, in each instance, treatment of said timing disc surface to renderthe same substantially light absorbtive or non-reflective is consideredto constitute a bit, it may be seen, for example, that bits are providedin the reference fluid band portions of bands 82 and 84 of thecolorimetric analysis channel bank portion 1, and that a bit is providedin the sample fluid band portion of band 82, only, of the colorimetricanalysis channel band portion 1. In like manner, it may be seen thatbits are provided in the reference fluid band portion of bands 76 and 84of the band portion for colorimetric analysis channel 8, while a bit isprovided in the sample fluid band portion of band 76, only, for thiscolorimetric analysis channel 8 band portion. By the above is believedmade clear that the light reflective characteristic of each of thecolorimetric analysis channel band portions formed on the disc surface74 may be effective to identify not only a different one of saidcolorimetric analysis channels, but to also identify the respectivereference or sample fluid band portion of said colorimetric analysischannel band portions.

Referring again to thefiber-optic or light pipe bundle 58 whichfunctions to transmit the light from the light source 34 to the timingdisc 74, it may be understood that the respective light exit ends of thelight pipes 60, 62, 64, 66 and 68 are arranged in substantially radialalignment relative to said disc surface with the light exit end of lightpipe 60 being arranged to illuminate an appropriately sized andconfigured spot on timing disc band 84, the light exit-end of light pipe62' being arranged to illuminate a like spot on timing disc band 82, thelight exit end of light pipe 64 being arranged to illuminate a like spoton timing disc band 80, the light exit end of light pipe 66 beingarranged to illuminate a like spot on timing disc band 78, and the lightexit end of light pipe 68 being arranged to illuminate a like spot ontiming disc band 76.

Further included in the detector and logic means timing and controlmeans 17 are a plurality of photosensitive devices which may, forexample, take the form of silicon photocells, as indicated at 86, 88,90, 92 and 94, respectively. A light pipe 96 extends, as shown, totransmit the light, if any, reflected from the spot illuminated on hand84 of the timing disc 74 by light pipe 60 for impingement upon thesilicon 7 photocell 86, while pipe 98 extends, as shown, to

transmit the light, if any, reflected from the spot illuminated ontiming disc band 82 by light pipe 62 for impingement upon the siliconphotocell 88. In like manner, light pipes 100, 102 and 104 are providedto extend, as shown, to transmit the light, if any, reflected from theilluminated spots on the respective timing disc bands 80, 78 and 76 forimpingement upon the respective silicon photocells 90, 92 and 94.

By the above described arrangement of the timing disc 74, the respectivesilicon photocells 86,88, 90, 92 and 94, and the relevant light pipes,the position of the rotating timing disc 74 at any point in time may beprecisely indicated by which of said silicon photocells is energized atsaid point in time. More specifically, with the timing disc 74 rotatingthrough the position thereof wherein the respective sample fluid bandportions of the colorimetric analysis channel 1 band portion are alignedwith the respective light exit ends of the light pipes 60, 62, 64, 66and 68, each of the silicon photocells 86, 90, 92 and 94, only, will beenergized. With the timing disc 74 rotating through the'position thereofin which the reference band portions of the colorimetric analysischannel 2 band portion are aligned for spot illumination from therespective light exists ends of said light pipes, silicon photocells 88,92, and 94, only, will be energized.

Further included in the detector and logic means timing and controlmeans 17 is a stationary light transmission directing disc 106 which, asbest seen in FIGS. 1 and 2, comprises a relatively large lighttransmission aperture 108 formed generally centrally thereof, and agenerally circular array of equally spaced light transmission directingapertures formed radially outwardly thereof adjacent the stationary discperiphery. For use in disclosed herein with colorimetric analysis meanshaving l2 colorimetric analysis channels, said generally circular arrayof light transmission directing apertures will be constituted by 24 ofthe same as indicated at 110 through 156 in FIG. 3.

The light pipes from the respective reference and sample fluid flowcells of the colorimetric analysis channels 1 through 12 whichconstitute the light pipe bundle 56 are respectively arranged so thatthe light exit ends thereof are each in substantial alignment with acorresponding one of the light transmission directing apertures 110through 156, so that the light exiting from each of said flow cells willbe transmitted to a different one of said light transmission directingapertures. More specifically, and with regard to the illustrated flowcells 22, 26, 28, and 24, light pipe 40 extends to transmit the lightfrom reference fluid flow cell 22 of channel 1 to light transmissiondirecting aperture 110, light pipe 38 extends to transmit the light fromsample fluid flow cell 26 of channel 1 to light transmission directingaperture 112, light pipe 44 extends to direct the light from referencefluid flow cell 24 of channel 2 to light transmission directing aperture114, while light pipe 42 extends to direct the light from sample fluidflow cell 28 of channel 2 to light transmission directing aperture 116.Each of the light pipes from the respective reference and sample flowcells of the remaining, non-illustrated colorimetric analysis channels 3through 12 may be understood to extend in like manner into operativerelationship with a different one of the remaining light transmissiondirecting aperture of the stationary disc 106, and the exact order oflight pipe light transmission directing aperture registration isindicated by the appropriate reference and sample colorimetric analysischannel designations as are provided on the light transmission directingdisc 106 in FIG. 2.

A generally V-shaped fiber optic light pipe scanner is indicated at inFIG. 1 and is affixed as indicated to the end of motor drive shaft 72,so as to be rotateable therewith in synchronism with the rotating timingdisc 74. As disclosed herein, the light pipe scanner 160 is effective toscan the respective light transmission directing apertures l10 through156 of the stationary light transmission directing disc 106 at a rate of30 times per second, and to transmit the light therefrom in appropriatesequence to the light sensitive detector means 14, as indicated by thedashed line extending therebetween. Each rotation of the rotating lightpipe scanner 160 is effective to transmit the light from the respectivereference and sample flow cells of colorimetric analysis channels Ithrough 12 in reference-and-sample-flow-cell alternating sequence as aseries of light pulses to the said detecting means.

To better illustrate this, it may be seen that with the respectivestationary light transmission directing disc 106 and the rotating lightpipe scanner 160 relatively positioned as depicted in FIG. 1 to alignthe light input end 161 of the latter with light transmission directingaperture 110, the light from reference flow cell 22 of colorimetricanalysis channel 1, which is transmitted to the disc on light pipe 40,will be transmitted therefrom through said light transmission directingaperture and, from the latter, by said light pipe scanner to the lightsensitive detector means 14; while, with said light pipe scanner rotatedthrough approximately 180 to align the light input end 161 thereof withthe light transmission directing aperture 136 of the disc 106, the lightfrom the non-illustrated sample flow cell of the colorimetric analysischannel 7 which may be assumed to be transmitted to said disc on lightpipe 50, will be transmitted therefrom in turn through the light pipescanner 160 for impingement upon said detector means.

Referring now to the digital logic means 16, the same comprises a seriesof switching networks of appropriate, passively operated electroniccomponents in the nature of diode networks as indicated schematically at163 which are operable in response to the optical outputs generated byrotation as described of the timing disc 74, as transduced intoelectrical outputs by the respective silicon photocells 86, 88, 90, 92and 94, to provide appropriate gating signal inputs to the read-outmeans operating circuit means 20 to control the operation of the latteras described in detail hereinbelow. To this effect, lines as indicatedat 164, 166, 168, and 172 direct the electrical outputs of therespective silicon photocells as electrical inputs to said logic meansto thus indicate to the latter the precise position of the rotatingtiming disc 74, and accordingly of the rotating light pipe scanner 160,at any given point in time.

By the above described arrangement of the respective stationary lighttransmission directing disc 106, the rotating timing disc 74, therotating light pipe scanner 160 and the synchronous rotation thereofwith said timing disc, all of the described light pipes, the respectivesilicon photocells 86, 88, 90, 92, and 94, and the operative connectionthereof as described to the digital logic means 16, the precise identityof the light impinging at any given point in time upon the lightsensitive detector means 14 insofar as the specific flow cell throughwhich the same has been passed is concerned, will be applied in the formof an appropriate electrical input signal to the digital logic means 16concomitantly with the impingement of said light on said detector means.More specifically, and with these components arranged as depicted inFIG. 1, the impingement of the light from reference fluid flow cell 22of colorimetric analysis channel 1 upon the detector means 14 willbeaccompanied by the concomitant energization of silicon photocells 90,92, and 94, only, with attendant application of the electrical outputstherefrom as electrical input signals on line 168, 170 and 172 to thedigital logic means 16 to positively identify this particular referencefluid flow cell 22 thereto. Inlike manner, with the light pipe scanner160 rotated through approximately 40 from the position thereof depictedin FIG. 1 to align the light inlet end 161 thereof with lighttransmission directing aperture 116 of the stationary disc 106 totransmit the light from sample fluid flow cell 28 of colorimetricanalysis channel 2 to the detector will be positively identified to thedigital logic rneans l6 I by the application of electrical inputsthereto on lines 164,166, 170 and 172, only.

' Referring now to the light sensitive detector means 14, the same maycomprise a single photomultiplier tube 180 which may, for example takethe form of that designated 4477 as manufactured and marketed by theRadio Corporation of America of Princeton, N.J., which is energized asindicated from any suitable source of negative input voltage. Aparticular advantage of the apparatus of the invention resides, ofcourse, in the fact that the detection of the analysis results from aplurality of colorimetric analysis channels through the use of one lightsensitive detecting means, only, is made possible. Of additionaladvantage with regard to the use of a photomultiplier tube in the lightsensitive detector means 14 as opposed, for example, to the moreconventional use of photosensitive devices in the nature ofphotoelectric cells or the like in colorimetric analysis apparatus,resides in the fact that since the gain of the photomultiplier tube 180is dependent primarily on, or proportional to, the input voltage, thesaid gain will be maintained relatively constant over the relativelyshort reference-sample interval through appropriate control of saidinput voltage. This is to say that although the gain of thephotomultiplier tube 180 may vary over relatively long time periods, thelinearity of the photomultiplier tube output will'not be significantlyaffected. Thus, the use of a relatively expensive, highly regulatedpower supply for said photomultiplier tube is not required.

' Referring now to the detector circuit means 18, the same may comprisea log diode 182 connected as shown in line 184 at the output side of thephotomultiplier tube 180, and a high input impedance amplifier 186connected as shown in series with the log diode 182 by line 188; Theamplifier 186 preferably exhibits a high input impedance and, as such,will preferably take the form of a PET follower, although amplifiershaving other and different configurations may, of course, be utilized. 7

A temperature stabilized resistance network is connected as shown acrossthe amplifier 186 by lines 190, 192 and 194, and comprises resistors 196and 198, and a temperature sensitive resistor 200 connected as shown inseries in lines 190 and 192. As a result of this provision of thetemperature stabilized resistance network, it may be understood that thetemperature-dependent transfer function of the amplifier 186 and thetemperature term in the equation for the voltage across the log diode182, as discussed in greater detail hereinbelow, will respectivelyappear in the numerator and denominator of such equation to effectivelycancel each other out to thereby render the operation of the log diode182 and the amplifier 186 substantially independent of ambienttemperature change.

As arranged and utilized herein, the log diode 182 and amplifier 186 arearranged to provide an output voltage signal V0 on line 202, forapplication as described in detail hereinbelow to the read-out meansoperating circuit means 20, which is directly proportional to theconcentration C of the fluid sample constituent of interestin eachinstance. More specifically, and considering for example the samplefluid flow cell 26 of colorimetric analysis channel 1, it may beunderstood that the relationship between the incident radiation appliedthereto from light source 34 on light pipe 38, and the exit radiationapplied therefrom by said light pipe to the rotating light pipe scannerand, from the latter, to the photomultiplier tube as described'in detailhereinabove, may be defined in accordance with Behrs law as follows:

EQUATION 1 P= P010 wherein P equals the exit radiation, Po equals theincident radiation, a equals the light absorbtivity of the fluid sampleof interest, b equals the flow cell light path length, and C equals theconcentration of the constituent of interest.

In like manner, the relationship between this exit radiation from theflow cell as applied to the photomultiplier tube 180, and the outputcurrent from the latter, may be expressed as follows:

EQUATION 2.

I K P wherein I is the photomultiplier tube output current, P is theexit radiation, and K, is a constant of the photomultiplier tube whichis determined in large measure bythe conversion efficiency and gainthereof.

The voltage drop across the log diode 182 which results from theapplication of the photomultiplier tube output current thereto may bedefined as follows:

EQUATION 3.

V0 KT/Q (K1P0I0 /I0) wherein V0 is said voltage drop, K equals Boltzmansconstant, T equals absolute temperature in degrees centigrade, Q is theconstant charge of an electron, and lo is a constant as determined bythe characteristics of said log diode.

From the above, the equation for the voltage drop across the log diode182 can be rewritten as follows:

EQUATION 4.

V KT/Q (I/Io More specifically, the voltage Vs across the log diode 182which results from impingement of the exit radiation P from a samplefluid flow cell in the nature of 26 and 28 upon the active surface ofthe photomultiplier tube 180 to generate a photomultiplier tube sampleoutput current Is, may be expressed as follows:

EQUATION 5.

Vs KT/Q (Is/I0) In like manner, the voltage Vr across said diode whichresults from the impingement of the exit radia tion P from a referencefluid flow cell such as 22 and 24 upon the active surface of thephotomultiplier tube 180 to generate a photomultiplier tube referenceoutput current Ir may be expressed as follows:

EQUATION 6.

Vr KT/Q (Ir/I0) As a result of the above, the Voltage Vs generated asdescribed in Equation 5 in response to the application of thephotomultiplier tube output current Is thereto will be directlyproportional to the concentration C of the constituent of interest inthe fluid sample then being colorimetrically analyzed. In like manner,the voltage Vr across the log diode 182 which is generated as describedin Equation 6 in response to the application of the photomultiplier tubeoutput current Ir thereto, will also be directly proportional to theknown concentration in the reference fluid of interest. In addition tothe provision of these log diode voltages which are directlyproportional in each instance to the respective sample and referencefluid concentrations such voltages will, in each instance, besubstantially independent of ambient temperature changes as a result ofthe provision, as described, of the temperature stabilization resistancenetwork across theamplifier 186.

The alternating appearance across the log diode 182 of reference andsample voltages Vr and Vs which will respectively be indicative of theresults of the colorimetric analyses effected in colorimetric analysischannels 1 through 12, and will appear in that order, will result in theapplication of said voltages on line 188 to the amplifier 186, theamplification thereof by the same, and the subsequent provision thereofas amplifier output voltages for application to the read-out meansoperating circuit means 20.

A particular advantage of the use of detector circuit means 18configured and operative, as described, to require the use of a singlelog diode 182, to perform a dual function in providing both thereference voltage Vr and the sample voltage Vs as separated in timethrough the time sharing of the said log diode, resides in the fact thatthe same eliminates the need for the use of a matched pair of log diodeshaving precisely matched scale factors to significant operational andeconomic advantage as should be readily apparent to those skilled inthis art. A further significant advantage of the use of detector circuitmeans 18 configured to utilize amplifier 186 substantially as a straightvoltage amplifier resides in the fact that concern need not be given tothe current noise characteristics of the latter to thus eliminate thedifficult requirement for the provision of an amplifier having both goodvoltage and current noise characteristics.

Referring now to the read-out means operating circuit means 20, therespective components thereof are specifically illustrated for thereadout of the results of the colorimetric analyses effected in channels1 and 2 only. A common operating circuit voltage signal input line orbus bar is is indicated at 204, and sample/hold modules 206, 208, 210and 212 are connected thereto as shown by voltage signal input lines214, 216, 218 and 220, it being understood that sample/hold modules 206and 208 are operative, as indicated, for colorimetric analysis channel1, while sample/hold modules 210 and 212 are operative, as indicated,for colorimetric analysis channel 2. The respective sample/hold modules206, 208, 210 and 212 are gated, as indicated, from the digital logicmeans 16 through the provision of mode-control logic input signals tosaid sample/hold modules from said logic means on lines 222, 224, 226and 228, respectively.

As utilized herein, the respective sample/hold modules 206, 208, 210 and212 may each be understood to be effective to acquire and track theappropriate analog input signals which are constituted by the respectivereference and sample amplifier output voltages Vr and Vs, and applied onthe respective operating circuit voltage signal input lines, and to holdthe respective instantaneous values of said analog input signals orreference and sample voltages upon command of the mode-control logicinputs from the digital logic means 16.

Each of said sample/hold modules may, for example, take the form of thatmanufactured and marketed by the Burr-Brown Research Corporation ofTuscon, Arizona as the Model 4034/25 sample/hold module. This particularsample/hold module comprises a unitygain noninverting device which isparticularly designed for medium-speed applications of the nature underdiscussion herein. In the sample mode, this module will track the analoginput signal and, when switched to the hold mode, will function to holdsubstantially constant the value of said analog input signal at the timeof such switching. A particular advantage of the use of this moduleresides in the fact that no external components are required and thatthe operation thereof may be readily effected through a simpleapplication of :l5 volts DC power thereto.

Further included in the read-out means operating circuit forcolorimetric analysis channel 1 is a differential amplifier 230, andlines 232 and 234 are provided as shown to apply the respective outputsignals from the channel 1 sample/hold modules 206 and 208 as inputsignals to said differential amplifier. In like manner, a differentialamplifier is indicated at 236 for colorimetric analysis channel 2, andlines 238 and 240 are provided as shown to apply the respective outputsignals from the channel 2 sample/hold modules 210 and 212 as inputs tothis differential amplifier.

Referring now to the read-out means 19, the same are constituted byappropriate colorimetric analysis results recording means which areprovided for each colorimetric analysis channel. More specifically, andfor colorimetric analysis channel 1, said read-out means may comprise astrip chart recorder 250 which may, for example, take the form of theDC, nullbalance type recorder shown and described in said US. Pat. No.3,241,432 which includes a strip chart 254 which is movable in theindicated direction, and a recording pen or stylus 256 which is operableto graph the results of the operation of the colorimetric fluid sampleanalysis performed in colormetric analysis channel 1. A line 258 isprovided to apply the output from the differential amplifier 230 as therecorder operating input to the stripchart recorder 250 for operation ofthe latter as described in greater detail hereinbelow.

A strip chart recorder of like construction and manner of operation isindicated at 258 and includes a moveable strip chart 260 and a recordingpen or stylus 262 which is operable to graph the results of theoperation of the colorimetric fluid sample analysis performed incolorimetric, analysis channel 2. To this effect, a line 264 is providedto apply the output, from the dif ferential amplifier 236 as therecorder operating input to the strip chart recorder 258. Although notspecifically illustrated, appropriate recorder means in the nature ofthe strip chart recorders 250 and 258 are included in the read-out means18 for each of the ten remaining colorimetric analysis channels 3through 12.

OPERATION In operation for use, for example, in the automatic sequentialdetermination through colorimetricquantitative analysis of a pluralityof different constituents, such as uric acid, glucose, blood ureanitrogen, billirubin, direct cholesterol, P total and direct billirubin,albumin, LDH, creatinine, total'protein and SGOT, respectively, of aseries of appropriately treated blood sample quotients which aresupplied thereto from sequentially operable fluid sample supply andtreatment means in the nature ofthose disclosed in said U.S. pat. No.3,241,432, the apparatus of the invention would be arranged so that thequotients of each of said blood samples, each of which had been treatedin a manner appropriate to the, colorimetric quantitative analysisthereof with respect to a different blood sample constituent ofinterest, are supplied in synchronism' to the respective fluid sampleflow cells for substantially concomitant flow therethrough.

More specifically, and as illustrated by way of example in FIG. 4B, itmay be seen that a series of blood sample quotientsas indicated at SUlthrough SUS, each of which had been treated in said fluid sample supplyand treatment means for colorimetric quantitative analysis thereof withregard to the uric acid'constituent thereof, and as separated, each fromthe other, by a segment of a suitable separating fluid SF, would besupplied as indicated for series flow through sample fluid flow cell 26of colorimetric analysis channel 1. As shown in FIG. 4A, a similarlyconfigured and dimensioned stream of a series of blood sample quotientsSAl through SaS, each of which had been appropriately treated in saidfluid sample supply and treatment means for colorimetric analysisthereof relative to thealbumin constituent thereof, would beconcomitantly supplied for flow through sample fluid flow cell 28 ofcolorimetric analysis channel 2. in like manner, similarly configuredstreams of series of blood sample quotients, each of which had beenappropriately treated for colorimetric analysis thereof with regard to adifferent constituent of each of the blood samples, would beconcomitantly flowed in "substantially identical phase relationshipthrough the remaining, non-illustrated sample fluid flow cells of theremaining colorimetric analysis channels 3 through 12.

Concomitantly with the flow as described of the respective blood samplequotient streams through the respective sample fluid flow cells of thecolorimetric analysis channels 1 through 12, fluid sample streams ofknown concentration appropriate to the colorimetric analysis for each ofthe constituents of interest would be flowed through the respectivereference fluid flow cells of said colorimetric analysis channels. Morespecifically, a reference fluid of known concentration appropriate tocolorimetric analysis for uric acid would be flowed through referencefluid flow cell 22 of colorimetric analysis channel 1, while a referencefluid of known concentration appropriate to colorimetric analysis foralbuminwould be flowed through reference fluid flow cell 24 ofcolorimetric analysis channel 2.

Concomitantly with this flow of the respective blood sample quotientstreams and reference fluids through the respective reference and fluidsample flow cells of the provided colorimetric analysis channels 1through 12, the timing disc 74 will be rotated by motor 70 at, forexample, 1,800 rpm to thus result in the sampling of the exit radiationP from each of said flow cells, and the transmission thereof forimpingement upon the photomultiplier tube 180, at a rate of 30 times persecond. Thus, and considering only the specifically i1- lustratedcolorimetric analysis channels 1 and 2, the

, light from the-reference fluid flow cell 22 of colorimetric analysischannel 1, the light from the sample fluid flow cell 26 of colorimetricanalysis channel 1 which is, of course, proportional in intensity to theamount of uric acid in the blood sample quotient Sul then flowingtherethrough, the light from reference fluid flow cell 24 ofcolorimetric analysis channel 2, and the light from sample fluid flowcell 28 of colorimetric analysis channel 2 proportional in intensity tothe amount of albumin contained in the blood sample quotient SAl thenflowing therethrough, will be transmitted in that order through therotating light pipe scanner for impingement upon the photomultipliertube 180. As a result, the reference and sample output currents Ir andIs from the photomultiplier tube 180, as defined hereinabove by Equation2, and the resultant reference and sample voltage outputs Vr and Vs fromthe amplifier 186, as defined hereinabove by Equations 5 and 6, andapplied to the common line or bus bar 204 of the recorder meansoperating circuit means 20, will respectively be directly proportionalto the known concentration in the uric acid reference fluid flowingthrough reference fluid flow cell 22, the uric acid concentration in theblood sample quotient SUI-flowing through samvple fluid flow cell '26,the known concentration in the albumin reference fluid flowing throughreference fluid flow cell 24, and the albumin concentration in the bloodsample quotient SAl flowing through sample fluid flow cell 28.

Concomitantly with this alternating transmission of light from therespective reference and sample fluid flow cells of colorimetricanalysis channels 1 and 2, the rotation at the same 1,800 rpm of thetiming disc 74 will be effective to operate the digital logic means 16to gate the respective sample/hold modules 206, 208, 210 and 212 inappropriate order. More specifically, as the light input end 161 of thelight pipe scanner 160 passes through alignment with the lighttransmission aperture 110 of the stationary disc 106 to thus transmitthe light from reference fluid flow cell 22 of colorimetric analysischannel 1 to the photomultiplier tube 180, the digital logic means 16will be effective to switch sample/hold module 206, only, on line 222from the sample mode thereof to the hold mode thereof whereby saidsample/hold module will hold constant the reference voltage Vr which isindicative of the known concentration in the reference fluid thenflowing through reference fluid flow cell 22 and will take the peaklevel thereof for application as a DC signal to the differentialamplifier 230 on line 232.

Subsequently, as the light input end 161 of the light pipe scanner 160passes through alignment with light transmission aperture 112 of thestationary disc 106 to thus transmit the exit radiation from samplefluid flow cell 26 of colorimetric analysis channel 1 to thephotomultiplier tube 180, the like rotation of the timing disc 74 willbe effective to operate the logic means 16 to switch the sample/holdmodule 208, only, on line 224 from the sample mode thereof to the holdmode thereof whereby the peak value of the sample voltage Vs from saidamplifier 186 which is indicative of the concentration of uric acid inthe blood sample quotient SUI then flowing through the sample fluid flowcell 26 will be held by said sample/hold module and applied as a DCsignal to the differential amplifier 230 on line 234.

In like manner, the digital logic means 16 will be operative to switchsample/hold module 210 from the sample mode to the hold mode thereofonly when the output reference voltage Vr from the amplifier 186 isindicative of the known concentration in the reference fluid flowingthrough reference fluid flow cell 24 of channel 2, and will be operativeto switch sample/hold module 210 from the sample mode thereof to thehold mode thereof only when the amplifier output sample voltage Vs isindicative of the concentration of albumin in the blood sample quotientSAl then flowing through sample fluid flow cell 28 of channel 2 forapplication, in each instance, of a DC signal of level corresponding tothe peak value of the relevant reference and sample voltages, todifferential amplifier 236 on lines 238 and 240.

This operation of the read-out means operating circuit means is believedmore clearly illustrated by the timing diagram of FIGS. 5A through 5Dwhich may be understood to be drawn to the same time scale and toillustrate the operation of the colorimetric analysis channel 1 portion,only, of the operating circuit means 20 for the colorimetric analysis ofthe blood sample quotient SUl. More specifically, and as seen in FIG.5A, the output reference voltage Vr which is applied from the amplifier186 to said operating circuit in response to the transmission of theexit radiation P from reference fluid flow cell 22 to thephotomultiplier tube 180 will consist of a series of spaced pulses asindicated at 270 and for rotation of the light pipe scanner at 1,800rpm, as discussed hereinabove, these pulses 270 would occur at the rateof 30 per second. The magnitude of each of the pulses 270 is, of course,substantially the same to thus clearly indicate the absence of anyvariation in the known concentration of the uric acid reference fluidflowing through said reference flow cell.

The waveform of the sample voltage Vs which is applied from theamplifier 186 to the operating circuit 20 in response to thetransmission of the exit radiation P from sample fluid flow cellconcomitant with the flow of the blood sample quotient SUI therethrough,to the photomultiplier tube is represented by the spaced pulses 722. Acomparison of FIGS. 5A and SB makes clear that the pulses 272immediately follow in point of time the pulses 270 due to the sequentialarrangement, in the direction of rotation of the light pipe scanner 160,of the respective light transmission apertures 110 and 112 in thestationary disc 106.

As each of the reference voltage pulses 270 is applied on line 214 tothe sample/hold module 206, and the latter appropriately switched by thedigital logic means 16 from the respective sample to hold modes thereofin synchronism with the application of these pulses thereto, this willresult in the holding by said sample/hold module of a substantiallyconstant DC level as indicated at 274 in FIG. 5C, and the applicationthereof on line 232 as one input to the differential amplifier 230.Conversely, the switching by the digital logic means 16 of thesample/hold module 208 from the sample to the hold mode thereofconcomitantly with the application of each of the sample voltage pulses272 thereto on line 216, will result in said sample/hold module holdinga DC level 275 which increases to a substantially constant, peak valueas indicated at 276 and decreases therefrom in response to thecorresponding increase and decrease in the peak values of the samplevoltage pulses 272 in accordance with conventional colorimetric analysisoperating characteristics, and the concomitant application of this DClevel 275 as the other input to differential amplifier 230 on line 234.

The concomitant application of the DC level 274 of FIG. 5C and the DClevel 275 of FIG. SD to the differential amplifier 230, and operation ofthe latter in the nature of a subtractor, will result in the provisionof a DC signal therefrom to the strip chart recorder 250 on line 258which is equal to the log of the reference current Ir, which flows fromthe photomultiplier tube 180 as a result of the transmission thereto ofthe exit radiation P from reference fluid flow cell 22, minus the log ofthe sample current Is, which flows from said photomultiplier tube uponthe transmission of the exit radiation P from the sample fluid flow cell26 thereto. The level of this DC signal will be directly proportional tothe difference between the fixed reference signal level as establishedby the known concentration in the reference fluid flowing throughreference fluid flow cell 22 and the concentration of uric acid in theblood sample quotient SUI flowing through fluid sample flow cell 26.More specifically, and referring again to Equations 5 and 6 as definedhereinabove, it may be understood that this DC output signal from thedifferential amplifier for analysis channel 1 may be defined as follows:

.EQUATION 7.

,V Vs-VZ KT/Q (log Is/To log Ir/I)=KT/Q log Is/Ir -This DC signal fromthe differential amplifier 230 is, of course, effective to operate therecording pen or stylus 256 of the strip chart recorder 250 to provide agraph on the recorder strip chart 254 which will bear a linearrelationship with the uric acid concentration of the bloodsamplequotient SUl to thereby enable the use of regular graphpaper, ratherthan log paper, in the formulation of said recorder strip chart, and themore convenient interpretation of the results provided thereon by saidrecording pen.

- The operation of the recorder operating circuit 20 and strip chartrecorders for the remaining colorimetric analysis channels 2 through 12is, of course, substantially identical to that described in detailhereinabove for colorimetric analysis channel 1. More specifically, theflow of each substantially phased group of 12 blood sample quotientsfrom a blood sample through the respective'sample fluid flow cells ofthe colorimetric analysischannels l-through 12, a graph linearly illustrating the amount of a different constituent-of interest of said bloodsample will be provided on the strip chart of each of thetwelve stripchart recorders which are included in the read-out means 18. Thesegraphs will, of course, be provided in series form for each of said con-'stituents. Thus, for example, and considering for purposes ofillustration only the five first analyzed blood samples as depicted inquotient form for colorimetric analysis channels 1 and 2, only, a seriesof graphs which are respectively representative of the uric acidconstituents of the blood sample quotients SUl through SUS of these fivefirst analyzed blood samples will be provided on the strip chart 254 ofstrip chart recorder 250, while a series of graphs indicating therespective albumin constituents of the blood sample quotients SAlthrough SAS of the same five first analyzed blood samples will beprovided on the strip chart 260 of the strip chart recorder 258. in likemanner, a series of graphs representing a different constituent ofinterest for each of the remaining blood sample quotients of said bloodsamples will be concomitantly provided on the remaining 10,non-illustrated strip chart recorders of colorimetric analysis channels3 through 12. Asa result, and assuming the apparatus to include 12colorimetric analysis channels as described, the analysis of 12 fluidsamples and the recording of the results thereof may be accuratelyeffected, through time sharing of the single light sensitive detectormeans and simultaneous recorder operation as described, in the timenormally required for such analysis and result recording for only asingle fluid sample, to thus provide for a very significant l,l00percent increase in the sample analysis rate. 1

- A particular advantage of the use, as described, of a single detectormeans in a ratio system resides in the fact that the gain of the formercan vary throughout a reasonable range without affecting the essentialoutput current ratio in each instance. Too, the use of a photomultipliertube for such detector means in a high quality ratio system may beunderstood to advantageously reduce noise to thus enable satisfactorydiscussed hereinabove is illustrated in FIG. 6. More specifically, andif it is assumed that channel 1, only, is to be utilized for theperformance of fluorimetric rather than, colorimetric analysis forquantitative determination, for example, of a blood sample constituentin the nature of SGPT, it may be understood that an additional radiationsource in the nature of a mercury arc source for the provision of therequisite ultra-violet radiation as indicated at 280 will be providedfor such fluorimetric analysis. In addition, light pipes of specializedconstruction as indicated at 380 and 40Q will be necessary for thetransmission of the ultra-violet radiation from said high-voltagemercury aresource to the respective reference and sample flow cells 22and 26 of the fluorimetric analysis channel 1. Light pipes 380 and .400may, for example, be made from a material having appropriate opticaltransmission characteristics in the nature of quartz.

The only other-change of significance which would be required for. theinclusion of a fluorimetric analysis channel 1 as depicted in FIG. 6would be the inclusion of suitable anti-log circuit means asindicatedschematically at 282 in common signal input line 204 of the operatingcircuit 20 as shown to convert the respective reference and sampleamplifier output voltages Vr and Vs which result from the operation ofthe fluorimetric analysis channel 1 into appropriate form for operationof the strip chart recorder 250 as described hereinabove prior to theapplication of said voltages to the respective channel 1 sample/holdmodules 206 and 208 of the read-out means operating circuit 20 and thesubsequent holding of the peak values of said voltages and applicationthereof as appropriate DC levels to the differential amplifier 230. Inthe case of fiuorimetric analysis, the exit radiation P from therespective sample and reference fluid flow cells 2 6 and 22 will bedirectly proportional to the constituent concentration C of interest.Since the log diode provides an output in terms of the absorbance whichis not linear with concentration, it becomes necessary to apply thisoutput across anti-log circuit means to return the same to the desiredform thereof which is directly proportional to the constituentconcentration C of interest for operation of the strip chart recorder250 as described.

In all respects, the construction and manner of operation of thecombined fluorimetric and colorimetric analysis means of FIG. 6 will besubstantially identicalto that of FIG. 1 with the additional obviousexception that the results provided by recording pen 256 on the stripchart 254 of channel 1 strip chart recorder 250 will, of course, beindicative of the quantity of a constituent of the series of bloodsample quotients flowed through sample fluid flow cell 26 as determinedby fluorimetric, rather than colorimetric, analysis means.

Another embodiment of the apparatus 10 of FIG. 1 is indicated generallyat 300 in FIG. 7, and it may be understood that like apparatuscomponents bear like reference numerals in each of FIGS. 1 and 7.

Referring now to FIG. 7, it may be seen that the primary distinction ofthe embodiment 300 resides in the fact that single element lighttransmission means are utilized therein to effect the transmission ofthe light from the light source 34 to the respective reference andsample flow cells. More specifically, said light transmission means takethe form of a generally Z-shaped light pipe 302, having a light inputend 304 and a light output end 306, which is arranged as shown to besupported from and rotatable with one extremity of the shaft 72 ofconstant speed drive motor 70 and functions, as discussed in greaterdetail hereinbelow, as a low loss light diffuser. A focusing lensassembly is indicated generally at 308 and is effective to focus thelight from the light source 34 to a very fine point for impingement uponlight input end 304 and attendant transmission through light pipe 302.

Stationary light transmission directing discs are indicated at 310 and312, respectively, and for use in a 12 channel system as described,would each take the form of the stationary timing disc 106 as best seenin FIG. 3. More specifically, each of the stationary light transmissiondirecting discs 310 and 312 would include, in the manner of disc 106, agenerally circular array of 24 alternating, equally spaced reference andsample light transmission directing apertures formed radially outwardlythereof adjacent the respective disc peripheries. As arranged, the discs310 and 312 respectively include apertures 314 and 316 found as showngenerally centrally thereof to enable the passage of drive motor shaft72 therethrough, and are, or course, relatively positioned so that thelike-numbered pairs of light transmission apertures which arerespectively formed therein are in substantial axial alignment asindicated for the pair of light transmission apertures 110, and for thepair of light transmission apertures 136.

A second, generally Z-shaped light pipe is indicated at 318 andcomprises a light input end 320 and a light output end 322. As shown,the light pipe 318 is supported from and rotatable with the otherextremity of drive motor shaft 72 in substantial alignment with therotating light pipe 306 so as to be rotatable in synchronism therewith.The light output end 306 of rotating light pipe 302 is, of course,disposed at substantially the same radius as is the circular array ofreference and sample light transmission directing apertures in thestationary disc 310; the same is, of course, true for light input end320 of the rotating light pipe 310 and the circular array of aperturesin stationary disc 312. In addition, light output and input ends arerespectively disposed as closely as practicable to the relevantstationary disc surfaces to maximize light transmission efficiency asshould be obvious. By this construction, rotation of shaft 72 willeffect synchronized scanning of the respective aligned pairs of lighttransmission apertures of the stationary light transmission directingdiscs 310 and 312 by the respective light output end 306 of rotatinglight pipe 302 and the light input end 320 of rotating light pipe 318.

The respective light input ends of the 24 light pipes which constitutethe fiber optic bundle 36 are, of course, arranged so that a differentone of the former extends in proper sequence as indicated into lighttransmitting relationship with the appropriate one of the reference andsample light transmission directing apertures in the stationary disc310; the relationship between the respective light output ends of theselight pipes as reformed into the fiber optic bundle 56 and therespective reference and sample light transmission apertures of thestationary disc 312 is the same as described hereinabove with referenceto FIGS. 1 and 3.

Shaft position indicator means are indicated schematically at 323 andare operatively associated as indicated by line 324 with drive motorshaft 72. The shaft position indicator means 323 preferably take anysuitable, readily commercially available or off-the-shelf self-containedform and, as such, may for example include a built-in light source. Asutilized in the apparatus 300 of FIG. 7, the shaft position indicatormeans 323 function, of course, in the manner of the detector and logicmeans timing and control means 17 of the apparatus 10 of FIG. 1 toclearly indicate at any point in time to the digital logic means 163 theidentity of the reference or sample flow cell through which the lightfrom light source 34 which is them impinging on the light sensitivedetector means 14 has passed. To this effect, said shaft positionindicator means may be connected to said digital logic means as againindicated by lines 164, 166, 168, and 172 extending therebetween.

The respective light sensitive detector means 14, detector circuit means18, read-out timing and control means 20 and read-out means 19 of FIG. 7are substantially the same as described in detail hereinabove withregard to FIG. 1, and are accordingly illustrated in simple block formin FIG. 7.

The operation of the apparatus 300 of FIG. 7 is substantially the sameas that of the apparatus 10 of FIG. 1 with the former functioning asdescribed, through the flow cell scanning function provided by thesynchronized driven rotation of rotating light pipes 302 and 318, topass the light from light source 34 in predetermined sequence throughthe respective reference and sample flow cells for sequentialimpingement upon the light sensitive detector means 14 and attendantprovision of the recorded sample analysis results of interest on therespective strip charts of the strip chart recorders which make up theread-out means 19.

Of particular advantage with regard to the apparatus 300 of FIG. 7 isthe increased optical power density or light energy transmitted to therespective flow cells through the focusing of the light from the lightsource 34 at a very fine point at the light input end 304 of rotatinglight pipe 302. In addition, and for use with a relatively large numberof analysis channels and with a light source 34 of relatively limitedsurface area, the apparatus 300 will render unnecessary the somewhatdifficult operative arrangement of the light input ends of a largenumber of light pipes relative to said limited light source surface areaand will, in addition, remove the attendant possibility of light sourceoverheating. Too, the use of the rotating, internally reflective lightpipes 302 and 318 and the focusing of the light from source 34 as a veryfine point at the light input end of light pipe 302 will result in thefunction of said light pipe as a very low loss diffuser to substantiallyminimize electronic noise as might otherwise result from operationalvibration of the light source filament and/or variation in positionalsensitivity of the photomultiplier tube photo cathode.

1. In a ratio system for the time sharing of multiple channel sampleanalysis means comprising a plurality of sample flow cells included in acorresponding plurality of sample analysis channels, each of said sampleflow cells containing a portion of a fluid sample to be analyzed withrespect to a particular constituent, reference flow cells included inselected ones of said analysis channels, means for optically scanningsaid sample flow cells and said reference flow cells, in turn, meansincluding a single light sensitive detector means responsive to saidscanning means for sequentially providing sample signals indicative ofthe respective concentrations of the particular constituents beinganalyzed in said sample flow cells and reference signals obtained by thescanning of said reference flow cells, means for comparing each of saidsample signals and an appropriate reference signal to provide ratiosignals indicative of the respective concentrations of eacH of saidconstituents in said fluid sample, and means for recording said ratiosignals.
 2. In a ratio system as in claim 1 wherein, said scanning meanscomprise means to transmit light energy through each of said sample flowcells and said reference flow cells, and means to transmit said lightenergies from said sample flow cells and reference flow cells forsequential impingement on said single light sensitive detector means. 3.In a ratio system as in claim 2 wherein, said single light sensitivedetector means comprise a single photomultiplier tube having a singlelog diode operatively associated therewith and across which the outputfrom said photomultiplier tube is applied to result in said referenceand sample signals, and further comprising, temperature stabilized meansoperatively associated with said single log diode and operable to rendersaid comparison between said reference and sample signals, substantiallyindependent of ambient temperature changes.
 4. In a ratio system as inclaim 2 wherein, said means to transmit light energy through each ofsaid sample flow cells and through each of said reference flow cellscomprise a single light energy source, fiber optic means to transmitsaid light energy from said source to and through said sample flow cellsand reference flow cells to light transmission directing means, saidscanning means being operatively associated with said light transmissiondirecting means and operable to scan the latter and sequentiallytransmit said light energies therefrom to said light sensitive detectormeans.
 5. In a ratio system as in claim 4 wherein, said scanning meanscomprise a rotating light pipe.
 6. In a ratio system as in claim 4wherein, said light transmission directing means comprise a disc havinga generally circular array of generally equally spaced lighttransmission directing apertures formed therein and corresponding toeach of said sample flow cells and said reference flow cells, and saidscanning means comprise a rotating light pipe the light input end ofwhich is operable to scan said array of light transmission directingapertures and the light output end of which is operable to sequentiallytransmit the light energies passing through each of said lighttransmission directing aperture to said light sensitive detector means.7. In a ratio system as in claim 2 wherein, said scanning means comprisea single light energy source, first and second light transmissiondirecting means, first scanning means to transmit said light energy fromsaid source to said first light transmission directing means, fiberoptic means to transmit said light energy from said first lighttransmission directing means to and through said sample flow cells andsaid reference flow cells to second light transmission directing means,and second scanning means operatively associated with said second lighttransmission directing means and operable to scan the latter andsequentially transmit said light energies therefrom to said lightsensitive detector means.
 8. In a ratio system as in claim 7 wherein,said first and second scanning means respectively comprise rotatinglight pipes which are rotatable in substantial synchronism.
 9. In aratio system as in claim 7 wherein, each of said first and second lighttransmission directing means, respectively, comprise discs havinggenerally circular arrays of generally equally spaced light transmissiondirecting apertures formed therein, there being one sample lighttransmission directing aperture and one reference light transmissiondirecting aperture formed in each of said discs corresponding to each ofsaid sample flow cells and said reference flow cells, said firstscanning means comprises a rotating light pipe the light input end ofwhich is effective to receive said light energies from said light energysource and the light output end of which is effective to scan said lighttransmission directing apertures of said first light transmissiondirecting disc to sequentially transmit said light energies to saidfiber optic means, and said second scanning means comprise a light pipewhich is rotatable in substantial synchronism with said first light pipeand the light input end of which is effective to scan said lighttransmission directing apertures of said second light transmissiondirecting disc to sequentially transmit the light energies therefrom tosaid light sensitive detecting means from the light output end of saidrotating light pipe.
 10. In a ratio system as in clam 2 furthercomprising a tunable light energy source, and means operativelyassociated with said scanning means and operable to vary the wavelengthof the light energies emitted from said tunable light energy source inaccordance with the particular one of said sample flow cells and saidreference flow cells then being scanned by said scanning means.
 11. In aratio system as in claim 2 further comprising sample supply andtreatment means having a manifold, at least said sample flow cells beingdisposed on said manifold.
 12. In a ratio system as in claim 11 wherein,said light sensitive detector means are disposed remotely of saidmanifold, and said means to sequentially transmit light energy througheach of said sample flow cells and said reference flow cells furthercomprise light source means disposed remotely of said manifold, andfiber optic means to transmit said light energy from said light sourcemeans to and through said sample flow cells and said reference flowcells, in turn, and therefrom to said remotely disposed light sensitivedetector means.
 13. In a ratio system as in claim 12 wherein, said lightsource means comprise a single light energy source.